Nearly 80% of people who have sustained a traumatic brain injury (TBI) report mild to moderate learning and memory impairments in the months to years following the initial brain trauma. Although there is some understanding of the changes that occur within the hippocampus after TBI, the underlying basis for learning deficits after TBI is still not completely understood. As a result, no FDA-approved pharmacological therapies are available to improve learning and memory deficits after TBI. The overarching objective of this proposal is to understand the chronic molecular mechanisms of learning and memory dysfunction after TBI and develop novel therapeutic strategies to translate to our chronic TBI survivors. An active area of both preclinical and clinical research is the use of cholinergic drugs to enhance cognition after TBI. Strong rationale exists for this therapeutic approach. Cholinergic receptors are important for modulating hippocampal long-term potentiation (LTP) and theta rhythm during spatial learning and cholinergic signaling is decreased after TBI. However, treatment with cholinesterase inhibitors or cholinergic receptor agonists have had limited clinical success. An exciting breakthrough has been the development of positive allosteric modulators of the ?7 nicotinic AChR (nAChR). Positive allosteric modulators enhance current only when the receptor is bound to agonist. This maintains the natural spatial and temporal integrity of cholinergic signaling. Using AVL-3288, a positive allosteric modulator of the ?7 nAChR, both hippocampal LTP and cognitive deficits were rescued in animals at 3 months after moderate fluid-percussion brain injury. Based on these preliminary data, the main hypothesis of this proposal is that targeting the ?7 nAChR with a positive allosteric modulator will be sufficient to rescue LTP, improve theta oscillations, and promote cognitive functioning in the chronic recovery period of TBI. To test this hypothesis, the following aims are proposed: 1) To determine if positive allosteric modulation of ?7 nAChRs is sufficient to restore hippocampal LTP and theta rhythms after TBI, 2) To determine if positive allosteric modulation of ?7 nAChRs improves chronic cognitive deficits after TBI, and 3) To mechanistically determine if positive allosteric modulation of ?7 nAChRs improves hippocampal synaptic plasticity and reduces chronic cognitive deficits after TBI through the ?7 nAChR. Using two preclinical models of TBI, fluid-percussion brain injury and controlled cortical impact, and two animal species, rats and mice, AVL-3288 will be thoroughly and critically evaluated to determine if this therapeutic approach is efficacious. In addition, multielectrode array recordings will be utilized to determine how ?7 nAChRs contribute to hippocampal circuitry changes after TBI. The clinical potential of these studies is very high given that AVL-3288 is already in Phase I clinical trials for cognitive impairment associated with schizophrenia. This proposal is supported by an interdisciplinary team with expertise in TBI, electrophysiology, cognition and pharmacology. Findings from this research proposal have the potential to be rapidly translated to clinical trials and will develop a new therapeutic for chronic TBI survivors to improve cognitio and quality of life.